Effect of different oral anticoagulants on cognitive function in patients with atrial fibrillation: A Bayesian network meta-analysis

Background: Atrial fibrillation (AF) is 1 of the most common types of arrhythmias. At present, the treatment for patients with AF mainly includes oral anticoagulants (OACs). Studies have shown that OACs are associated with cognitive decline in patients with atrial fibrillation; however, there is a lack of relevant evidence. This study used Bayesian network meta-analysis (NMA) to investigate the effects of different oral anticoagulants on cognitive decline in patients with AF. Methods: We systematically searched for clinical studies on oral anticoagulants in patients with AF in PubMed, Web of Science, Embase, and the Cochrane Library as of July 3, 2023. Cochrane’s randomized controlled trial bias risk assessment tool and the Newcastle–Ottawa Scale were used to assess the bias risk of the included studies. The main outcome measure was decreased cognitive functioning. Results: Ten studies were included, including 2 RCTs and 7 RCSs, including 882,847 patients with AF. Five oral anticoagulants and 2 anticoagulants were included: VKAs (especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel. The results of the mesh meta-analysis showed that VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF (OR = −1.19, 95% CI (−2.35, −0.06), P < .05) (Table 5). The top 3 drugs in terms of the probability of reducing the incidence of cognitive impairment in patients with AF with different oral anticoagulants were VKAs (87%), rivaroxaban (62.2%), and dabigatran (60.8%). Conclusion: Based on the results of this study, VKAs may be the best intervention measure for reducing the risk of cognitive decline in patients with AF. Owing to the limitations of this study, more high-quality randomized controlled trials with large sample sizes and multiple centers are required to provide more evidence.


Introduction
Atrial fibrillation (AF) is 1 of the most common types of arrhythmias.This refers to the sudden occurrence of abnormal electrical pulses in the atrium that exceed the regulation of the natural pacemaker in the heart.AF occurs when the natural pacemaker of the heart is no longer able to control its rhythm.At this point, regular and orderly atrial electrical activity is lost, leading to the occurrence of irregular fibrillation waves.This condition is a serious disorder of atrial electrical activity.
AF can cause irregular and usually abnormally rapid contraction of atrial myocardial cells, leading to various symptoms including irregular heart rate, palpitations, dizziness, shortness of breath, and fatigue. [1]AF mainly occurs in the elderly (>70 yrs old) and in people with lifestyle-related diseases such as hypertension, diabetes, and obesity. [2]With the increase in the aging population, the incidence rate of AF is also rising.The incidence rate of AF is estimated to increase by more than 60% by 2050. [3]AF may seriously affect the quality of life of patients because it may lead to serious complications such as stroke, heart failure, cognitive decline, and cardiac arrest, which will lead to an increase in the incidence rate and mortality. [4]A systematic review suggested that AF increases the risk of cognitive impairment, all-cause dementia, vascular dementia, and Alzheimer's disease (AD) (RR = 2.2, 95% CI = 1.4-3.5,P < .05).
At present, the treatment for patients with AF mainly includes controlling the heart rate, converting to sinus rhythm, and anticoagulant therapy, among which permanent AF patients require long-term anticoagulant therapy. [5,6]ntithrombotic drugs, especially oral anticoagulants are the main treatment for most patients with AF.Vitamin K antagonists (VKAs), and direct oral anticoagulants (NOAC), such as dabigatran, rivaroxaban, and apixaban, are widely used in the treatment of AF with good results. [7]Aspirin and clopidogrel are anti aggregation drugs, which are widely used in clinical anticoagulation therapy and therefore included in the study for comparison.Research has shown that abnormal hemostasis can identify the risk of dementia, whereas anticoagulation can prevent the occurrence of dementia. [8]Multiple systematic reviews have shown that OACs can significantly reduce the risk of cognitive impairment.For example, Zong Yuan Lee's study showed that NOAC had a better effect on reducing dementia than warfarin (OR = 0.65, 95% CI = 0.34, 1.25, P < .05). [9]Pajaree Mongkhon research has shown that OAC can reduce the risk of dementia (RR = 0.79, 95% CI = 0.67-0.93,P < .05). [10]Cheng et al found that NOAC can reduce the risk of cognitive impairment compared to warfarin (HR = 0.51, 95% CI = 0.37-0.71,P < .05). [11]However, the effectiveness of different anticoagulants in reducing cognitive impairment remains unclear.
NMA is a state-of-the-art evidence-based technique that uses direct or indirect comparisons to compare the effects of multiple interventions on diseases and estimate the hierarchical order of each treatment. [12]Therefore, in this study, we used a NMA to compare the cognitive outcomes of different oral anticoagulants (warfarin, dabigatran, rivaroxaban, and apixaban) and aspirin, in patients with AF and provide evidence-based recommendations for patients and clinical physicians.

Registration
This study was conducted according to the reporting guidelines of system review and mesh meta-analysis (PRISMA-NMA) and has been conducted in PROSPERO (https://www.crd.york.ac.uk/PROSPERO/#myprospero) Conduct prospective registration (ID: CRD42023420169).

Retrieval strategy
Research papers were retrieved from PubMed, EMbase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP database, and SinoMed.The search encompassed the period from database inception to July 3, 2022.Retrieval strategies were systematically constructed using the PICOS framework as follows: study participants: patients with AF; intervention measures: oral anticoagulants; control group: oral anticoagulants (different from the intervention group); outcome indicators: cognitive impairment; study type: clinical research.Table 1 shows the retrieval strategy used in this study (PubMed).

Exclusion criteria
Studies with incomplete data; Nonclinical studies, such as reviews, abstracts, letters, and plans.Research on intervention measures that do not meet the inclusion criteria.

Literature screening
Automatic plagiarism-checking function of the Endnote literature management software was used to screen the literature.Two researchers (Ning WL and Wang SH) initially identified duplicate literature.Subsequently, they screened the remaining articles by reading the title and abstract to determine inclusion and exclusion.Finally, the entire text was read to further confirm inclusion.Two researchers independently screened and compared the remaining studies.If they were the same, they were included in the study.If they differed, they were discussed and resolved by a third researcher (Tang HQ).

Data extraction
Two researchers (Ning and Wang) designed a data extraction table based on the information needed for the study, including the author, year, study participants, sex, sample size, intervention measures, follow-up time, outcome indicators, quality evaluation information, and other relevant content.When there is inconsistency in the information extracted by 2 people, they should first discuss and resolve it with each other.If this cannot be resolved, the decision should be made through discussion.

Quality evaluation
Two researchers (Ning WL and Wang SH) independently conducted bias risk assessment.Randomized controlled trials were evaluated using the Cochrane Handbook 5.1.0version of the ROB tool for assessing bias risk in randomized controlled trials. [13]It includes the following 7 fields: random sequence generation; allocation concealment; participant and subject blind methods; result evaluation blind method; completeness of result data; selective reporting; and other biased sources.The experiment was divided into 3 levels according to the number of components that may have a high ROB: high risk (5 or more), moderate risk (3 or 4), and low risk (2 or fewer).
Cohort studies were evaluated using the Newcastle-Ottawa Scale for bias risk assessment. [14]This table represents the score with ★, with a maximum score of 9 ★, and 7 to 9 ★ are relatively high-quality articles.This table was used in this study with several evaluation items assigned to each aspect.When the assigned items meet the requirements, they are represented by ★, with the highest comparability being 2 ★.

Statistical analysis
In the correlation study, all variables were countable, calculated using the odds ratio (OR) and 95% confidence interval (CI).Owing to potential differences between studies, we chose a random-effects model for analysis instead of a fixed-effects model. [15]We used the gem package of R4.2.0 software, and according to the PRISMA-NMA manual, [16,17] Markov chain Monte Carlo simulation chains were used in a Bayesian framework for network meta-analysis (NMA) aggregation and analysis.We used the node method to quantify and prove the consistency between indirect and direct comparisons, calculated through the instructions in the Stata software, if the P-value was >.05.A consistency check was conducted. [18]he Stata software was used to present and describe the network diagrams of the different exercise interventions.In the generated network diagram, each node represents a different motor intervention and control condition, and the lines connecting the nodes represent direct positive comparisons between interventions.The size of each node and width of the connecting lines are directly proportional to the number of studies. [19]he efficacy of each indicator was sorted to obtain the surface under the cumulative ranking (SUCRA) and plot the probability ranking in a graph.A percentage was used to represent SUCRA.A larger percentage indicates that the intervention is more effective and a value of zero indicates that the intervention is completely ineffective.Although SUCRA can be effectively rephrased as a percentage of the effectiveness or acceptability of exercise interventions, these scores should be interpreted with caution unless there are actual clinical differences between the interventions. [20] Results

Literature screening results
In total, 2080 studies were retrieved.A total of 976 duplicate references were excluded: 52 were excluded by reading titles and abstracts, and 42 were excluded by reading the entire text (reasons included incomplete data, noncompliance with the outcome indicators included in this study, conference papers, abstracts, plans, and interventions not included in this study).The remaining ten references were included in this study (Fig. 1).

Basic features
We included a total of 10 studies, including 2 RCTs and 7 RCSs, including 882,847 patients with AF.Five oral anticoagulants and 2 anticoagulants were included: VKAs (especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel.The indicators were all indicators of cognitive impairment, with 2 studies using the Monthly Cognitive Assessment (MMSE) and 8 studies calculating the incidence of dementia.Five studies were conducted in the Americas, 1 in East Asia, and 3 in Europe.Patient characteristics are shown in Table 2.

Quality evaluation
The bias risk assessment results for cohort studies showed that 1 study scored 8 points and 7 studies scored 9 points, indicating high literature quality.Bruno Caramelli et al's study showed insufficient information in Blinding of output assessment (detection bias), while Nahal Mavaddat et al's study did not provide sufficient information in Random sequence generation (selection bias), allocation consideration (selection bias), and blinding of output assessment (detection bias).See Tables 3 and 4.

Mesh meta-analysis results
The complete NMA diagram is shown in Figures 2A and 2B.The network evidence graph showed that there was a closed loop in the study, and the p-values of all indirect and direct comparisons between studies were tested for consistency and inconsistency, with P-values >.05, indicating that the consistency effect between studies is acceptable.The results of the mesh meta-analysis showed that other VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF (OR = −1.19,95% CI (−2.35, −0.06), P < .05)(Table 5).The top 3 probability rankings of different OACs in reducing the incidence of cognitive impairment in patients with AF were VKAs (87%), rivaroxaban (62.2%), and dabigatran (60.8%), as shown in Figure 2B and Table 6.

Discussion
This study included 10 clinical studies on the treatment of AF with OACs, involving 5 OACs and 2 anticoagulants: VKAs(especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel.The results of the mesh meta-analysis showed that other VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF compared to warfarin.There was no significant difference in the risk of cognitive impairment between the other OACs (P > .05).The SUCRA ranking results showed that the VKAs ranked first, indicating that they may be the best OACs and can provide a reference for clinical medication.

Dementia
Leif Friberg [27] Sweden 2018 RCS AF NA 227646 NOAC/Warfarin 96 months Dementia Malini Madhavan [28] USA 2018 RCS AF 71.9 ± 12.0, 70.sphingolipids (components of the myelin sheath and neuronal membrane), and in neuronal survival by biologically activating vitamin K-dependent proteins. [32]VKAs can interfere with the vitamin K cycle and reduce the availability of the active form of vitamin K (hydroquinone) in the brain. [33]It regulates the biological activation of 2 types of vitamin K-dependent proteins, namely Gas6 (growth arrest-specific gene 6) and protein S. [32,34] Gas6 participates in chemotaxis, mitosis, cell growth, and differentiation.Amyloid protein-β-induced apoptosis is a hallmark of AD.Protein S protects neurons during ischemia/hypoxia injury. [35]Additionally, vitamin K regulates the metabolism of sphingolipids, which are key participants in neuronal ation, differentiation, aging, cell-cell interactions, and transformation. [32,34]Changes in sphingolipid metabolism may also be related to neurodegenerative diseases such as AD.Importantly, the use of VKAs has been shown to alter the distribution of sphingolipids. [36]he connection between VKA use and cognitive impairment has not been fully elucidated.Some clinical studies have demonstrated a correlation between VKAs and cognitive decline.Antoine Brangier collected information on the use of VKAs among 378 elderly outpatient patients.After 12 and 24 months of follow-up, overall cognitive performance and executive function were evaluated using simplified mental state examination and positive assessment group FAB scores, respectively.The results showed that the use of VKAs was associated with lower FAB scores at baseline (adjusted for β=− 2.1, P = .026)and correlated with a decrease in FAB scores after 24 months (pre-adjusted β= − 203.6%, P = .010).The use of VKAs was not associated with any changes in the minimental state examinations scores at baseline (P = .655),12 months (P = .603),or 24 months (P = .021).Compared with the control group, elderly patients who used VKAs experienced more severe executive dysfunction at baseline and decreased executive power within 24 months. [37]C é drive Anweiler classified 266 elderly patients based on their cognitive impairments.The routine use of VKAs should be examined by asking patients, relatives, and family doctors.Through investigation, it was found that, compared to participants without cognitive impairment, participants with a mini-mental state check of ≤25 used VKAs more frequently (P = .038).The use of VKAs was independently associated with cognitive impairment (fully adjusted OR = 17.4 [95% CI: 1.4-224.2],P = .028). [38]Guyaine Ferland measured the exposure of VKAs and platelet aggregation inhibitors (another anticoagulant) in 7133 elderly thrombotic patients.Participants underwent cognitive assessment every 2 years at baseline and within 10 years.The results showed a significant correlation between poor performance on the VKAs treatment and the Benton visual retention test (adjusted mean difference, −0.29; P = .02in the multivariate model) for evaluating visual memory at baseline and the Isaacs set test (adjusted mean difference, −1.37; P = .0009)to evaluate the language fluency.VKAs treatment was not associated with the overall cognitive function of minimental state examinations, nor was it associated with the rate of decrease in scores on all 3 subsequent cognitive tests. [39]The above clinical studies have found a correlation between VKAs and cognitive decline, which may increase the risk of cognitive decline.This is inconsistent with the results of this study, indicating that the correlation between VKAs and cognitive decline is controversial and requires further clinical research.

Strengths and limitations
Strengths of this study: For the first time, we conducted a NMA of the effects of different OACs on cognitive function in patients with AF, comparing the differences in cognitive function between different OACs in patients with AF.We strictly followed the bias risk assessment method used in clinical research to evaluate the quality of the included studies.We conducted (PRISMA-NMA) according to the reporting guidelines of the system review and mesh meta-analysis and conducted prospective registration with PROSPERO in advance.
Limitations of this study: The number of included studies was relatively small, and there were differences in the selection of efficacy evaluation criteria, patient characteristics, sample size, and outcome indicators in the included studies.These confounding factors may have an impact on the results.The methodological quality of some studies is low, and these factors may have an impact on the strength of the evidence.

Figure 2 .
Figure 2. (2A) NMA figure (The blue circle represents the number of users, with larger circles indicating greater participant numbers.Lines represent direct study comparisons; thicker, continuous lines indicate a higher number of studies).(2B) SUCRA plot(The larger the area under the curve, the more effective the intervention measures are).NMA = network meta-analysis.

Table 2
Basic characteristics of included studies.